Anesthetic halogenated cyclobutanes

ABSTRACT

Certain halogenated cyclobutanes are disclosed which possess utility as inhalation anesthetics. They are: 1-chloro-1,2,2trifluorocyclobutane, 1,4-dichloro-1,2,2-trifluorocyclobutane, 1chloro-1,2,2,4-tetrafluorocyclobutane, 1,4-dichloro-1,2,2,4tetrafluorocyclobutane, 1-chloro-2,2,3,3-tetrafluorocyclobutane, 1,2,2,3,3-pentafluorocyclobutane, 1-chloro-1,2,2,3,3pentafluorocyclobutane, 1,2,2-trifluorocyclobutane, 1-chloro2,3,3-trifluorocyclobutane, 1-chloro-2,4,4-trifluorocyclobutane, 1-bromo-1,2,2-trifluorocyclobutane, 1-bromo-2-methyl-1,4,4trifluorocyclobutane and 1-bromo-2-chloro-1,4,4trifluorocyclobutane.

United States Patent Holdsworth et al.

in] 3,870,797 Mar. 11, 1975 ANESTHETIC HALOGENATED CYCLOBUTANES [75] inventors: Robert S. Holdsworth; Gerald Joseph ONeill, both of Arlington; Charles William Simons, Bedford, all of Mass.

[73] Assignee: W. R. Grace & Co., Cambridge,

Mass. by said Simons 22 Filed: Sept. 7, 1973 21 Appl. No.: 394,975

Related US. Application Data [63] Continuation-impart of Ser. No. l70,280, Ser. No. l7(l,33l, and Ser. No. 170,293, all Aug. 9, I97], said $61. No. l7(),280 is a continuation-in-part of Ser. No. 91,521, Nov. 20, I970, and said Ser. No. 170.33] is a continuation-in-part of Ser. No. 93,437, Nov. 27. I970, and Ser. No. l4l,934, May 10, 1971,

all abandoned.

{52] US. Cl. 424/352 [5i] Int. Cl A6lk 27/00 Field of Search 424/352 [56] References Cited OTHER PUBLICATIONS Larsen, Fluorine Chemistry Review, Vol. 3, 1969, pages I and 34.

Primary E.\'aminer.lerome D. Goldberg Attorney, Agent, or FirmArma nd McMillan; C. Edward Parker [57] ABSTRACT fluorocyclobutane, l,2,2-triflu0rocycl0butane, lchl0ro2,3,3-trifluorocyclobutane, l-chloro-2,4,4- trifluorocyclobutane, l-bromo-l ,2,2- trifluorocyclobutane, l-bromo-Z-methyl-l ,4,4- trifluorocyclobutane and 1-brom0-2-chl0ro-1,4,4 trifluorocyclobutane.

14 Claims, N0 Drawings 1 ANESTI-IETIC HALOGENATED CYCLOBUTANES CROSS-REFERENCE TO RELATED APPLICATIONS This is a continuation-in-part of applications Ser. No. 5

of Ser. No. 93,437 filed on Nov. 27, 1970 and Ser. No.

141,934 filed May 10, 1971 all these applications have been abandoned.

THE PRIOR ART In the continuing search for safe, effective inhalation anesthetics that began with the introduction of chloroform in the middle of the last century, surprisingly few compounds have qualified for that drastic yet delicate role. This penury derives in part from the unpredictable chemical and physiological properties and behavior of plausible compounds such as for instance the lower halogenated alkanes, as well as from the lack of understanding of the mode of action of anesthetics in general. While some superficial parameters have been evolved to gauge a few of the necessary properties of a good inhalation anesthetic; e.g., a certain oil-water distribution coefficient and the negative influence of fluorine as opposed to that of chlorine, the discovery of a useful anesthetic agent remains beyond the scope of the routine expertise of both the chemist and the physiologist.

Thus, it is, for instance, that while cyclopropane is recognized as an effective if inflammable anesthetic, one of its higher water-insoluble homologs, cyclopentane, has no medical use. As to cyclobutanes, a recent review of the state of the art [Larsen, E. R., Fluorine Chemistry Reviews, Vol. 3, pages 1 and 34 (1969)] is no more enlightening in its report that of three closely related fluorocyclobutanes, one is said to possess anesthetic properties (1,2-dihydrohexafluoro-) while the others are toxic 1,2-dich1orohexafluoro-) and inactive (octafluoro-) respectively.

Burns et al., the original investigators of the cyclobutanes reviewed by Larsen, conclude that It is suggested that none of the compounds is sufficiently promising to justify further investigation at this time [Burns et al., Anesthesia 19 (2), 168 (1964)]. With respect to 1,Z-dihydrohexafluorocyclobutane, the only anesthetic halocyclobutane of the art, the judgment just quoted has found ample support as demonstrated in Example XIV of the present specification. Kranz and Rudo, after an extensive review of the pharmacological properties of fluorine compounds, also conclude that cyclic halogenated compounds tend to be toxic. [Handbuch Exp. Pharm. 20 (1), 541 (1966)].

SUMMARY OF THE INVENTION It has now been discovered that certain l-chloro- 1,2,2-trifluoro-cyclobutanes possess inhalation anes thetic properties and do not cause convulsions and death when administered in concentrations within the useful range. The compounds found to possess this utility are l-chloro-l,2,Z-trifluorocyclobutane, 1,4- dichloro-l ,2,Z-trifluorocyclobutane, 1-ch1oro-l,2,2,4- tetrafluorocyclobutane, 1,4-dichlorol ,2,2,4-tetrafluorocyclobutane, 1-chloro-2,2,3 ,3-tetrafluorocyclobutane, 1,2,2,3,3-pentafluorocycl0butane, 1- chloro- 1 ,2,2,3,3-pentafluorocyclobutane, 1,2,2- trifluorocyclobutane, 1-chlor0-2,3,3- trifluorocyclobutane, 1-chloro-2,4,4- trifluorocyclobutane, 1-bromo-1,2,2-

trifluorocyclobutane, trifluorocyclobutane trifluorocyclobutane DETAILED DESCRIPTION The compounds of this invention can be prepared by cyclizing appropriately selected ethylenic compounds in an autoclave according to the method of Coffman et al. [.I. Am. Chem. Soc. 71, 490 (1949)]. The ethylenic compounds are typically charged into the autoclave and heated at a suitable temperature; c.g., at about 200C, for a period of, for example, about 7 hours at autogenous pressure. When the reaction is complete. the autoclave is cooled and gaseous substances are evacuated through a cold trap. The liquid content is then removed and subjected to a preliminary distillation followed by final purification by means of preparatory scale vapor phase chromatography or by other suitable techniques. Compounds of sufficiently high purity for anesthetic use are obtained in this manner.

1-bromo-2-methyl-1,4,4-

and 1bromo-2-chloro-1,4,4-

The ethylenic compounds employed in synthesizing the anesthetic products of this invention are listed in the Table 1 along with some of the physical properties of the products. In the case of new compounds, the cyclic structure as well as the number and type of ring substituents were confirmed by analysis of the NMR spectra.

Table 1 Synthesis and Physical Properties o1 Anesthetic Compounds Bum-g Ex. cyclobutane Reactants Density Point .1) o 1 l-ch1oro-1,2,2 C1FC=|CF 1.347 78 C trifluoroethy ene a ll 1,4-dichloro- C1FC==CF I 1.5-l-f (a) 104 C 1,2,2.4-tetralluorovinyl chloride 1.5+) (h) 107 C lll 1-ch1oro-1.2.2,4- C1FC=C'F d 1.467" C tetralluorovinyl lluorl e u o 1V 1.4-dicl1loro- CIFtZ (F 1.547- 90.5 C 1.2.2,4-tetrulluoro- C1I H. In C V l-chloro- (F Cll' l I I 1.437- 74 2,2,3,3-tetra1luorov|ny or out u I V1 1,2,2,3.3-penta11uoro- CF1 .=(F. I 1.441" 5()52C vinyl fluoride u O VII 1-ch1oro-2,3,3- CHF=CF., 1.4+ 8082 C vinyl chloride Table 1 -Continued Synthesis and Physical Properties of Anesthetic Compounds Cycli/ntiun l'ullowcd It reduction with lithium aluminum hydride,

The anesthetic compounds shown in Table l are clear liquids at room temperature. They can be stored in containers of the type commonly used for conventhen calculated from these minimum concentrations. The data obtained with the compounds of Examples l to XIII are presented in Table 2 along with, for compartional anesthetics of comparable boiling point; e.g., hal- 20 ison purposes, results obtained from similar testing of othane, and they can be administered by means of apparatus or machines designed to vaporize liquid anesthetics and mix them with air, oxygen or other gaseous combinations in amounts capable of supporting respil,2-dihydrohexafluorocyclobutane, the compound of the prior art, a closely related analog, I,1,2,2-tetrafluorocyclobutane, and another chlorofluoro anesthetic, l,I,2-trichloro-2,3,3-trifluorocyclobutane.

Table 2 Anesthetic Data Ex. Cyclobutane C5" LCM) Al ("/1 volume) I l-chlorol ,2,2-tril'luoro- I71 4-67: 4+ II I ,4-dichlorol ,2,2-trifluoro-, 0.2% 0.8% 4

h.p. 104C I,4-dichloro-l,2,2-trifluoro-. 0.271 I 2/: 6 h.p. I07C III I-chloro-l,2,2,4-tetralluoro- 0,571 3-3.5'/1 6+ IV I ,4-dichloro- I ,2.2,4-tetrafluoro- 0.43-271 24W: I V l-chloro-2,2,3,3-tetrafluoro- 0.5% 2.5% 5 VI 1.2.2.3,3-pentalluoro- 37! 6% 2+ VII I-chIoro2,3,3-trifluoro- 0.75-171 4+/: 4+ Vlll l-chloro-l,2,2,3,3-pentafluoro- 2'7: l()'/( 5 IX l-chloro-2,4,4-trifluoro- W1 29; 2+ X 1,2,2-trifluoro- 47! 8% 3+ XI l-bromo-l,2,2-trifluoro- 0.5'/1 3.5% 7+ XII l-bromo-2-methyl- 0.5-] "/1 I .5- I .7592

1,4,4-trifluoro- XIII I-bromo-2-chloro- 0.2/( 0.5% 2

I ,4,4-trifluoro- XIV I,2-dihydrohexafluoro-, h.p. 63 1.9% l,2-dihydrohexafluoro-, h.p. 26 l0.57( XV I, I ,2,2-tetrafluoro- 471 I 2% XVI l,I,2-trichloro-2.3,3-trifluoro- 0,1271 I7: 5

Where two percentages are given. thc actual vapor concentration lies between the two \alues.

ration. It is further contemplated that the compounds herein disclosed may be used in admixture with phar- ANESTHETIC PROPERTIES The physiological effects of the compounds of this invention were demonstrated upon mice, using a standard test for evaluation ofinhalation anesthetics similar to that described by Robbins [Pharmacology and Experimental Terapeutics 86, 197 (1946)]. In this test, mice were exposed to the compounds for a period of 10 minutes in a rotating drum. Observations were then made of the pinch reflex, the corneal reflex and the return of the righting reflex. At least four graded doses were employed to determine the minimum concentration required to anesthetize 50% of the mice used (AC and the minimum concentration required to kill 50% ofthe mice (LC The anesthetic index (Al) was The results shown in Table 2 demonstrate that the compounds tested in Examples l to XIII are potent anesthetics with differing but generally high margins of safety, as indicated by the anesthetic index values (Al). In this respect, it would be noted that halothane, an important conventional acyclic halogenated anesthetic, has an index of about 3 when tested in the present manner. The values given for the anesthetic concentrations of the cisand trans isomers of 1,2-dihydrohexafluorocyclobutane in Example XIV are those reported by Burns et a] [Anesthesia l9 (2), and 176 (1964) and 16 (l), (1961)] and reviewed in Larsen and Kranz & Rudo cited earlier.

While each of the compounds shown in the table has proved capable of inducing a state of general anesthesia in air-breathing mammals from which the animals soon recover provided that lethal concentrations of anesthetic vapors (LC are not reached, it has been determined on retesting the hexafluorocyclobutanes of the art in the manner of Examples I to XIII, XV and XVI, that the animals used in such tests die within 30 hours from the time of exposure although they at first apparently recover successfully from the state of anesthesia induced by the compounds in question. The same delayed death phenomenon has been observed in tests with compound XVI, a compound which otherwise would have been considered an excellent anesthetic in terms of potency and safety margin.

In contrast to these findings, all test mice used in Examples l to Xlll were still living 1 week after exposure.

Similarly, the tetrafluoro compound of Example XV, which might have been considered as a satisfactory, safe weak anesthetic on the basis of a quick determination of its anesthetic and lethal concentrations (AC 4%; LC 12; Al, 3), proved to be a convulsant on further observation. This compound, which is one of the numerous halogenated cyclobutanes that have been found deleterious, is of particular interest in that its close structural relationship to the 1,2-dihydrohexafluorocyclobutane isomers of the art and to the useful pentafluoro (Ex. VI) and trifluoro (Ex. X) homologs disclosed above provides a good illustration of the unpredicatability in physiological behavior in the field of anesthesia.

What is claimed is:

l. The process of inducing anesthesia in a mammal which comprises administering by inhalation to said mammal an effective quantity for inducing anesthesia of a cyclobutane selected from the group consisting of l-chloro-l ,2,Z-trifluorocyclobutane, 1,4-dichlorol,2,2-trifluorocyclobutane, l-chloro-l ,2,2,4-tetrafluorocyclobutane, l,4-dichloro-l,2,2,4-tetrafluorocyclobutane, l-chloro-2,2,3,3-tetrafluorocyclobutane, l,2,2,3,3-pc-ntafluorocyclobutane, l-chlor0-1,2,2,3,3- pentafluorocyclobutane, l,2,Z-trifluorocyclobutane, l-chloro-2,3,3-trifluorocyclobutane, l-chloro-2,4,4- trifluorocyclobutane. 1-bromo-1,2,2- trifluorocyclobutane, l-bromo-2-methyl-l ,4,4-

trifluorocyclobutane and l-bromo-2-chloro-l,4,4- trifluorocyclobutane.

2. The process of claim 1 wherein the cyclobutane administered is l-chloro-l,2,2-trifluorocyclobutane.

3. The process of claim 1 wherein the cyclobutane administered is l,4-dichloro-l,2,2- trifluorocyclobutane.

4. The process of claim 1 wherein the cyclobutane administered is l-chloro-l,2,2,4-tetrafluorocyclobutane.

5. The process of claim 1 wherein the cyclobutane administered is l,4-dichloro-l,2,2,4-tetrafluorocyclobutane.

6. The process of claim 1 wherein the cyclobutane administered is lchlor0-2,2,3,3-tetrafluorocyclobutane.

7. The process of claim 1 wherein the cyclobutane administered is l,2,2,3,3-pentafluorocyclobutane.

8. The process of claim 1 wherein the cyclobutane administered is l-chloro-2,3,3-trifluorocyclobutane.

9. The process of claim I wherein the cyclobutane administered is l-chloro-l ,2,2,3,3-pentrifluorocyclobutane.

10. The process of claim 1 wherein the cyclobutane administered is l-chloro-2,4,4-trifluorocyclobutane.

11. The process of claim 1 wherein the cyclobutane administered is l,2,Z-trifluorocyclobutane.

12. The process of claim 1 wherein the cyclobutane administered is l-bromo-l,2,2-trifluorocyclobutane.

13. The process of claim 1 wherein the cyclobutane administered is l-bromo-Z-methyl-l ,4,4- trifluorocyclobutane.

14. The process of claim 1 wherein the cyclobutane administered is l-bromo-2-chloro-l ,4,4- 

1. THE PROCESS OF INDUCING ANESTHESIA IN A MAMMAL WHICH COMPRISES ADMINISTERING BY INHALATION TO SAID MAMMAL AN EFFECTIVE QUANTITY FOR INDUCING ANESTHESIA OF A CYCLOBUTANE SELECTED FROM THE GROUP CONSISTING OF 1-CHLORO-1,2,2TRIFLUOROCYCLOBUTANE, 1,4-DICHLORO-1,2,2TRIFLUOROCYCLOBUTANE, 1-CHLORO-1,2,2,4TETRAFLUOROCYCLOBUTANE, 1,4-DICHLORO-1,2,2,4TETRAFLUROCYCLOBUTANE, 1-CHLORO-2,2,3,3TETRAFLUOROCYCLOBUTANE,1,2,2,3,3-PENTAFLUOROCYCLOBUTANE, 1CHLORO-1,2,2,3,3-PENTAFLUOROCYCLOBUTANE, 1,2,2TRIFLUOROCYCLOBUTANE, 1-CHLORO-2,3,3-TRIFLUOROCYCLOBUTANE, 1CHLORO-2,4,4-TRIFLUOROCYCLOBUTANE, 1-BROMO-1,2,2TRIFLUOROCYCLOBUTANE, 1-BROMO-2-METHYL-1, 4,4TRIFLUOROCYCLOBUTANE AND 1-BROMO-2-CHLORO-1,4,4TRIFLUOROCYCLOBUTANE.
 1. The process of inducing anesthesia in a mammal which comprises administering by inhalation to said mammal an effective quantity for inducing anesthesia of a cyclobutane selected from the group consisting of 1-chloro-1,2,2-trifluorocyclobutane, 1,4-dichloro-1,2,2-trifluorocyclobutane, 1-chloro-1,2,2,4-tetrafluorocyclobutane, 1,4-dichloro-1,2,2,4-tetrafluorocyclobutane, 1-chloro-2,2,3,3-tetrafluorocyclobutane, 1,2,2,3,3-pentafluorocyclobutane, 1-chloro-1,2,2,3,3-pentafluorocyclobutane, 1,2,2-trifluorocyclobutane, 1-chloro-2,3, 3-trifluorocyclobutane, 1-chloro-2,4,4-trifluorocyclobutane, 1-bromo-1,2,2-trifluorocyclobutane, 1-bromo-2-methyl-1,4,4-trifluorocyclobutane and 1-bromo-2-chloro-1,4,4-trifluorocyclobutane.
 2. The process of claim 1 wherein the cyclobutane administered is 1-chloro-1,2,2-trifluorocyclobutane.
 3. The process of claim 1 wherein the cyclobutane administered is 1,4-dichloro-1,2,2-trifluorocyclobutane.
 4. The process of claim 1 wherein the cyclobutane administered is 1-chloro-1,2,2,4-tetrafluorocyclobutane.
 5. The process of claim 1 wherein the cyclobutane administered is 1,4-dichloro-1,2,2,4-tetrafluorocyclobutane.
 6. The process of claim 1 wherein the cyclobutane administered is 1-chloro-2,2,3,3-tetrafluorocyclobutane.
 7. The process of claim 1 wherein the cyclobutane administered is 1,2,2,3,3-pentafluorocyclobutane.
 8. The process of claim 1 wherein the cyclobutane administered is 1-chloro-2,3,3-trifluorocyclobutane.
 9. The process of claim 1 wherein the cyclobutane administered is 1-chloro-1,2,2,3,3-pentafluorocyclobutane.
 10. The process of claim 1 wherein the cyclobutane administered is 1-chloro-2,4,4-trifluorocyclobutane.
 11. The process of claim 1 Wherein the cyclobutane administered is 1,2,2-trifluorocyclobutane.
 12. The process of claim 1 wherein the cyclobutane administered is 1-bromo-1,2,2-trifluorocyclobutane.
 13. The process of claim 1 wherein the cyclobutane administered is 1-bromo-2-methyl-1,4,4-trifluorocyclobutane. 